Host-Microbiota-Diet Interactions in Metabolic Syndrome and IBD

人类越来越多地受到慢性炎症性疾病的困扰，包括炎症性肠病。 (IBD)和代谢综合征(Met Syn)，统称为一系列代谢问题 与肥胖有关。这项申请寻求续期的拨款发展了我们的假设，即IBD和 Met Syn具有疾病病理生理学共性，即肠道微生物区系管理不善 在推动炎症方面发挥关键作用，炎症是两种疾病状态的核心。的一个主要特点是 在IBD和Met Syn中观察到的微生物区系失调是一种更具侵略性的微生物区系，它会侵占 在肠道上皮细胞上，这可能与其促进炎症有关。一种诱导的方法 微生物群入侵及其炎性后果是通过食用缺乏可发酵的饮食造成的 纤维。我们发现，这种低纤维饮食诱导的侵蚀涉及微生物区系的消融。 天然淋巴样细胞(ILC)产生的IL-22，通常用于加强上皮。因此， 用可发酵纤维菊粉而不是不可溶/不可发酵纤维纤维素来丰富这种日粮， 恢复IL-22的产生，减少微生物群的侵袭，改善低度炎症，以及 保护小鼠免受饮食诱导的Met Syn。然而，我们也观察到，用丰富的精致饮食 一些可发酵纤维也导致了一些IL-22非依赖性的负面后果，包括加剧 实验诱导的结肠炎和促进肝癌，从而突出表明，目前，我们缺乏 安全设计促进健康食品的知识。因此，我们的核心总体假设是 对膳食纤维如何影响宿主-微生物区系关系的机械理解将有助于努力 设计饮食和/或更安全有效地设计促进肠道微生物区系有益的食品 相互作用，从而改善肠道炎症及其相关疾病状态，包括IBD和Met Syn。 我们将通过3个具体目标来研究这一假说：目标1：确定滋养微生物区系的方法 纤维可导致ILC介导的IL-22的产生。目标2：定义心理学能力的潜在机制 预防代谢综合征和结肠炎。目标3：开发结肠靶向递送IL-22的方法 并研究其恢复肠道健康和改善炎症性疾病的能力。

Humanity is increasingly afflicted by chronic inflammatory diseases, including inflammatory bowel disease (IBD) and metabolic syndrome (Met Syn), which collectively refers to the constellation of metabolic problems associated with obesity. The grant this application seeks to renew has developed our hypothesis that IBD and Met Syn share commonalities of disease pathophysiology, namely that poor management of gut microbiota plays a key role in driving inflammation that is central to both disease states. A central feature of the microbiota dysbiosis observed in both IBD and Met Syn is a more “aggressive” microbiota that encroaches upon the gut epithelium, which is likely germane to its promotion of inflammation. One means of inducing microbiota encroachment and its inflammatory consequences is via consumption of a diet lacking fermentable fiber. We found that such low fiber diet-induced encroachment involves ablation of microbiota-mediated innate lymphoid cell (ILC) IL-22 production that normally serves to fortify the epithelium. Consequently, enriching such diets with the fermentable fiber inulin, but not the insoluble/non-fermentable fiber cellulose, restored IL-22 production, reduced microbiota encroachment, ameliorated low-grade inflammation, and protected mice from diet-induced Met Syn. However, we’ve also observed that enriching refined diets with some fermentable fibers also induced some IL-22-independent negative consequences, including exacerbating experimentally-induced colitis and promoting liver cancer thus highlighting that, at present, we lack the knowledge to safely engineer health-promoting foods. Hence, our central overall hypothesis is that better mechanistic understanding of how dietary fiber impacts the host-microbiota relationship will inform efforts to design diets and/or more safely and effectively engineer foods that promote beneficial intestine-microbiota interactions, thus ameliorating gut inflammation and its associated disease states, including IBD and Met Syn. We will investigate this hypothesis via 3 specific aims: Aim 1: Identify means by which nourishing microbiota with fiber results in ILC-mediated IL-22 production. Aim 2: Define mechanism underlying psyllium’s ability to protect against metabolic syndrome and colitis. Aim 3: Develop a means of targeted delivery of colonic IL-22 and investigate its ability to restore gut health and ameliorate inflammatory diseases.